title: A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells.
abstract: Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC(50)=1.39 μM) than in DU145 (IC(50)=2.94 μM) and PC3 cells (IC(50)=3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50)=1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.
authors.affiliation: Molecular Inflammation Research Institute for Aging Intervention and College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeong-gu, Busan 609–735, South Korea.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Patra
authors.forename: Umasankar
authors.initials: U
authors.lastname: De
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kang
authors.forename: Ji Mim
authors.initials: JM
authors.lastname: Kim
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Ahn
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D055162:Biocatalysis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D016166:Free Radical Scavengers; C559681:MHY336; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; C002385:linsidomine; D008981:Molsidomine; D004250:DNA Topoisomerases, Type II